E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Synovial sarcoma and Myxoid/Round Cell Liposarcoma (MRCLS) |
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E.1.1.1 | Medical condition in easily understood language |
Synovial sarcoma and Myxoid/Round Cell Liposarcoma (MRCLS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042863 |
E.1.2 | Term | Synovial sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073137 |
E.1.2 | Term | Myxoid liposarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of NY-ESO-1-Specific (c259) T Cells, alone or in combination with other anti-cancer agents, in HLA-A*02:01, HLA-A* 02:05 and/or HLA-A*02:06 participants with NY-ESO-1- and/or LAGE-1a positive solid tumors |
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E.2.2 | Secondary objectives of the trial |
- To further evaluate the efficacy of NY-ESO-1 Specific (c259) T Cells alone or in combination with other anti-cancer agents in HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 participants with NY-ESO-1 and/or LAGE-1a positive solid tumors
- To evaluate the safety and tolerability of NY-ESO- 1 Specific (c259) T Cells alone or in combination with other anti-cancer agents in HLA-A*02:01, HLA-A*02:05 and/or HLA-A* 02:06 participants with NY-ESO-1- and/or LAGE-1a positive solid tumors |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
SUBSTUDY 1: LETETRESGENE AUTOLEUCEL (LETE-CEL, GSK3377794) IN NY-ESO-1 POSITIVE PREVIOUSLY UNTREATED ADVANCED (METASTATICOR UNRESECTABLE) SYNOVIAL SARCOMA AND MYXOID/ROUND CELL LIPOSARCOMA
SUBSTUDY 2: LETETRESGENE AUTOLEUCEL (LETE-CEL, GSK3377794) IN NY-ESO-1 POSITIVE PREVIOUSLY TREATED ADVANCED (METASTATIC OR UNRESECTABLE) SYNOVIAL SARCOMA OR MYXOID/ROUND CELL LIPOSARCOMA |
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E.3 | Principal inclusion criteria |
1.Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. For participants <18 years of age (or the legal minimum age in the relevant country) their legal guardian must give informed consent. Pediatric participants will be included in age-appropriate discussion in order to obtain assent. 2.Participant must be ≥10 years of age at the time of signing the informed consent. Participant scheduled to receive clinical drug product supply must also weigh ≥40 kg. For participant scheduled to receive commercial drug product supply and weighing <40kg, the Investigator must also consult with the Medical Monitor prior to inclusion. 3.Participant has a diagnosis of synovial sarcoma or myxoid/round cell liposarcoma, confirmed by local histopathology and with evidence of translocation per below: – for synovial sarcoma, the presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented in the pathology report as t (X;18)) is required; – for myxoid/round cell liposarcoma, the presence of a translocation t (12;16)(q13;p11) or the variant translocation t (12;22)(q13;q12) is required. 4.Participant has high-risk locally advanced (i.e. deeply seated, high grade, positive margins, large [≥5 cm], or locally recurrent) synovial sarcoma or myxoid/round cell liposarcoma. 5.Participant with synovial sarcoma or myxoid/round cell liposarcoma who is a)for Substudy 1:Newly diagnosed, previously untreated OR b)Relapsed after surgery or radiotherapy for localized disease OR c)Relapsed ≥1 year after adjuvant/neoadjuvant therapy for localized disease for Substudy 2: Participant is either currently being treated with or has completed at least one standard of care treatment including anthracycline-containing regimens (e.g. doxorubicin alone, doxorubicin with ifosfamide, etc.) for advanced (metastatic or inoperable) disease. 6.Male or female. Contraception requirements will apply at the time of leukapharesis and treatment. 7. A representative tumor tissue specimen (archived or fresh biopsy) with associated pathology report should be available to perform NY-ESO-1 antigen expression analysis, unless a recent NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, has already been performed under a separate GSK-sponsored protocol or under another substudy. For guidance on acceptable specimen material see Tumor Biopsies under Section 5.1 Leukapheresis Eligibility Screening All the Inclusion Criteria in 1-7 must apply again prior to leukapheresis. In addition, the following criteria must also apply: 8.Life expectancy ≥24 weeks 9.Participant has advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma. Unresectable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise. 10.Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a designated central lab prior to leukapheresis. NOTE: An HLA test result from the same designated central laboratory, following the same procedures, and performed under a separate GSK-sponsored protocol or under another substudy is acceptable 11.Participant’s tumor has been pathologically reviewed by a designated central laboratory with confirmed positive NY-ESO-1 expression defined as ≥30% of cells that are 2+ or 3+ by immunohistochemistry. NOTE: A NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, and performed under a separate GSK-sponsored protocol or under another substudy is acceptable. 12.Left ventricular ejection fraction ≥45% with no evidence of clinically significant pericardial effusion. 13.Performance status: for participants <16 years of age, Lansky >60, or for participants ≥ 16 and <18 years of age, Karnofsky >60, or for participants ≥ 18 years of age, Eastern Cooperative Oncology Group (ECOG) of 0-1. 14.Participant must have adequate organ function and blood cell counts, within 7 days prior to the day of leukapheresis procedure (or first day of lymphodepletion during Treatment fitness assessment), as indicated by the following laboratory values in protocol. 15.Participant is fit for leukapheresis and has adequate venous access for the cell collection. 16.Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
For a detailed list of Inclusion Criteria's please refer to the protocol |
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E.4 | Principal exclusion criteria |
1.Participant has been previously treated for advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma. 2.Central nervous system (CNS) metastases. 3.Any other prior malignancy that is not in complete remission. Exceptions include: a.completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (e.g. melanoma in situ, basal cell carcinoma, prostate cancer in-situ, periosteal osteosarcoma) b.previous malignancies that have been definitively treated, and have been in remission for 5 years may be enrolled upon consultation with sponsor Medical Monitor or designee 4.Previous treatment with genetically engineered NY-ESO-1 specific T cells. 5.Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody. 6.Prior gene therapy using an integrating vector. 7.Previous allogeneic hematopoietic stem cell transplant. 8.Clinically significant systemic illness: a.serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the participant’s ability to tolerate protocol therapy or significantly increase the risk of complications OR b.prior or active demyelinating disease Leukapheresis Eligibility Screening Participants are not eligible for leukapharesis if any of the Exclusion criteria 1-8 apply. Please note in particular that mandatory washout period restrictions must be respected (Table 5) before starting leukapheresis. In addition, participants are not eligible for leukapharesis if any of the following criteria apply: 9.Participant has history of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn’s disease, systemic lupus) requiring steroids or other immunosuppressive treatments. 10.Uncontrolled intercurrent illness including, but not limited to: a.Ongoing or active infection b.Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 /Class 4 c.Uncontrolled clinically significant arrhythmia d.Acute coronary syndrome (angina or myocardial infarction) in last 6 months e.Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded; however, participants cannot be oxygen dependent) 11.Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per Investigator assessment). NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice or cirrhosis. 12.QTc >480 msec NOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP). 13.Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, other agents used in the study. 14.Pregnant or breastfeeding females (due to risk to fetus or newborn). 15.Prior/Concomitant Therapy: a.Any prior treatment-related toxicities must be CTCAE (Version 5.0) ≤ Grade 1 at the time of initiating study intervention (except for non-clinically significant toxicities e.g., alopecia, vitiligo). Participants with Grade 2 toxicities that are deemed stable or irreversible (e.g. chemotherapy related arthritis or tendinitis, skin discoloration or erythema) can be enrolled. b.Other standard of care lines of therapy are allowed only if guidelines and washout periods are followed as described in protocol. 16.Investigational treatment within 30 days or 5 half-lives (whichever is shorter) prior to leukapheresis. Investigational vaccines (other than NY-ESO-1 vaccines that are not allowed) must follow the washout period specified in Table 5. Exceptions to this rule must be evaluated by the Investigator in agreement with the Sponsor’s Medical Monitor (or designee). 17.Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or HTLV as defined in protocol.
For a detailed list of Exclusion Criteria's please refer to the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR) per RECIST (assessed by investigator for Substudy 1 and assessed by independant review committee for Substudy 2) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To further evaluate the efficacy of NY-ESO-1 - Time to Response (TTR) - Duration of Response (DoR) - Disease Control Rate (DCR) - Progression Free Survival (PFS) - Overall Survival (OS) for Substudy 2
To evaluate the safety and tolerability of NYESO-1 -Frequency and severity of Adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI; as defined in protocol) -Laboratory parameters -Replication Competent Lentivirus (RCL) -Instances of Insertional oncogenesis (IO)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United States |
France |
Germany |
Italy |
Netherlands |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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This master protocol will end as of the last visit of the last participant in the last sub-study, or when all participants have met their respective substudy end criteria including those who have died, withdrawn consent or are lost to follow-up. For full details please refer to the protocol P37. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |